Genome-wide regulatory network governing neuronal mRNA translation.

控制神经元 mRNA 翻译的全基因组调控网络。

• 批准号: 8533035
• 负责人: JOSHUA T DUBNAU
• 金额: $ 45.37万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8533035
• 关键词: Biological Models; Brain; Cognition; Communities; Defect; Drosophila genus; Ensure; Fragile X Syndrome; Genes; Genetic; Genetic Translation; Genome; Human; Individual; Inherited; Learning; Memory; Mental Retardation; Methods; Modification; Nervous system structure; Neurons; Process; Property; Protein Biosynthesis; Proteins; Regulation; Regulator Genes; Reporter; Research; Resources; Site; Synapses; Translations; empowered; experience; gene conservation; genome-wide; in vivo; relating to nervous system; response

DESCRIPTION (provided by applicant): This proposal seeks to develop a genome-wide in vivo approach to define the suite of regulatory interactions controlling mRNA translation in the nervous system. A fundamental property of the brain is that perceptual experiences drive modifications in number and strength of synaptic connections among neurons. These synapse modifications, which are thought to be neural correlates of memory and cognition, require synthesis of specific proteins at individual synaptic sites in response to neural activity. The mechanisms governing this local synthesis of synaptic proteins are poorly understood, but its disruption can have severe consequences. This proposal describes a method that will provide individual genetic reporters of neural translation for each gene, and will identify the suite of regulatory mechanisms. The approach involves several steps. First is a method to create in vivo reporters of translation for each gene. Second is a high-throughput strategy to identify the set of genes whose translation is governed by a particular regulator. As a proof of principle, we will define the targets of 5 key translational regulators, including Fragile-X protein. Fragile-X is the most common inherited form of mental retardation. This proposal also will generate a resource that will empower the research community to identify the set of targets for any translational regulator. Our method takes advantage of the exceptional genetic manipulability of the Drosophila model system. The high degree of conservation of gene regulatory mechanisms and function ensures that much of what we learn will be transferable to humans.

描述（由申请人提供）：该提案旨在开发一种全基因组体内方法来定义控制神经系统中 mRNA 翻译的一套调控相互作用。大脑的一个基本特性是感知体验驱动神经元之间突触连接的数量和强度的变化。这些突触修饰被认为与记忆和认知的神经相关，需要在各个突触位点合成特定蛋白质以响应神经活动。人们对控制突触蛋白局部合成的机制知之甚少，但其破坏可能会产生严重后果。该提案描述了一种方法，该方法将为每个基因提供神经翻译的个体遗传报告，并确定一套调节机制。该方法涉及几个步骤。第一种方法是为每个基因创建体内翻译报告基因。其次是高通量策略，用于识别其翻译受特定调节器控制的基因组。作为原理证明，我们将定义 5 个关键翻译调节因子的靶标，包括 Fragile-X 蛋白。 Fragile-X 是最常见的遗传性智力障碍。该提案还将产生一种资源，使研究界能够确定任何转化监管机构的目标集。我们的方法利用了果蝇模型系统卓越的遗传可操作性。基因调控机制和功能的高度保守性确保了我们学到的大部分知识都可以转移到人类身上。

项目成果

Transposable elements in TDP-43-mediated neurodegenerative disorders.

TDP-43 介导的神经退行性疾病中的转座元件。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Li, Wanhe;Jin, Ying;Prazak, Lisa;Hammell, Molly;Dubnau, Josh
• 通讯作者: Dubnau, Josh

Systems memory consolidation in Drosophila.

果蝇的系统内存整合。

• 发表时间: 2013-02
• 影响因子: 5.7
• 作者: Dubnau, Josh;Chiang, Ann
• 通讯作者: Chiang, Ann

Activation of transposable elements during aging and neuronal decline in Drosophila.

果蝇衰老和神经元衰退过程中转座元件的激活。

• 发表时间: 2013-05
• 影响因子: 25
• 作者: Li, Wanhe;Prazak, Lisa;Chatterjee, Nabanita;Grüninger, Servan;Krug, Lisa;Theodorou, Delphine;Dubnau, Josh
• 通讯作者: Dubnau, Josh